B‐cell signaling in persistent polyclonal B lymphocytosis (PPBL)

• Published in: Immunology and cell biology 2016-10, Vol.94 (9), p.830-837
• Main Authors: Voelxen, Nadine, Wehr, Claudia, Gutenberger, Sylvia, Keller, Baerbel, Erlacher, Miriam, Dominguez‐Conde, Cecilia, Bertele, Daniela, Emmerich, Florian, Pantic, Milena, Jennings, Stefanie, Rakhmanov, Mirzokhid, Foerster, Christian, Martens, Uwe M, Platzbecker, Uwe, Peter, Hans‐Hartmut, Fisch, Paul, Boztug, Kaan, Eibel, Hermann, Salzer, Ulrich, Warnatz, Klaus
• Format: Article
• Language: English
• Subjects: Adult; B-Lymphocytes - immunology; CD40 Antigens - metabolism; Child, Preschool; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation; Humans; Lymphocyte Activation - immunology; Lymphocytosis - genetics; Lymphocytosis - immunology; Male; Middle Aged; Phenotype; Phosphorylation; Receptors, Antigen, B-Cell - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - immunology
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2016.46

Persistent polyclonal B lymphocytosis (PPBL) is a benign hematological disorder characterized by a selective expansion of circulating polyclonal marginal zone (MZ)‐like B cells. Previous reports demonstrated that cases of PPBL showed poor activation, proliferation and survival of B cells in vitro, yet the underlying defect remains unknown. Here we report for the first time an attenuated activation of the canonical NF‐κB (nuclear factor of kappa light polypeptide gene enhancer in B cells) and mitogen‐activated protein kinase/extracellular signal‐regulated kinase pathway after CD40 stimulation. This defect was selective, as alternative NF‐κB signaling after CD40 stimulation and both B‐cell receptor‐ and Toll‐like receptor 9‐mediated activation remained unaffected. Reduced canonical NF‐κB activation resulted in decreased IκBα and CD40 expression in resting cells. In PPBL patients, expression of Bcl‐xL in MZ‐like B cells did not increase upon activation, consistent with the high apoptosis rates of PPBL‐derived B cells that were observed in vitro. The B‐cell phenotype of mice with selective knockouts of early components of the CD40 signaling pathway resembles PPBL, but sequencing corresponding genes in sorted MZ‐like B cells of PPBL patients did not reveal relevant genetic alterations. Nevertheless, the frequently observed mutations in early signaling components of the NF‐κB pathway in MZ lymphomas underline the relevance of our findings for the pathogenesis of PPBL.